Long term objective: To develop peptide-based interleukin 6 (IL-6)-specific inhibitors for the treatment of diseases in which IL-6 might contribute to the pathogenesis, such as rheumatoid arthritis. Peptides with IL-6 antagonist activity in vitro will then be tested in animal models for efficacy. Since metabolic stability may be a concern when peptides are administered in vivo, an analog program will be initiated to modify the most active peptides to maximize their activity. If these attempts are successful, the design of additional peptidomimetics is planned to lead to orally active compounds. Principles established in this research project could be used for the design of antagonists for other cytokines, and thus, will provide useful information for the design of a new class of pharmaceutical compounds for selective manipulation of the immune system. Specific Aims: (1) To identify short sequences of 10-15 amino acids that are crucial for ligand-receptor interaction of IL-6. The identified peptides will be synthesized by solid phase synthesis and tested for IL-6 antagonist activity in IL-6-specific bioassays. (2) To test the hypothesis that structural prediction is useful for the identification of receptor-ligand interaction sits. To synthesize analogs of active peptides to identify the optimum epitope and its minimal structural requirements. (3) To generate polyclonal anti-peptide antibodies for further characterization of the epitopes of interest.